Previously, our SPORE investigators (5 projects) successfully translated their basic findings into 3 Phase 1 interventional clinical trials, a 42-patient glioma tissue analysis defining loss of a key growth regulatory mechanism and a 332 patient case-control genetic epidemiology survey defining significant associations of two HLA phenotypes with either indolent or rapid glioma progression. The themes of this, new competitive renewal SPORE application include: Anti-apoptosis Inhibition, Oncolytic Virus therapy, Antibody-mediated Therapy, Apoptosis, and Autophagy. Four translational research projects are proposed, each of which will initiate one or more interventional clinical trials within a 3- 5 year time frame. These include: 1)Targeted' Intervention of the JAK2/STAT3 Signaling Axis for Anaplastic Glioma Therapy \o develop a rational basis for inhibiting the JAK2/STAT3 pathway using small molecule inhibitor drugs to improve conventional therapeutic outcomes; 2) Optimized Chimeric HSV for Anaplastic Glioma Therapy will develop a clinical application for a cGMP RAID-produced chimeric herpes simplex virus is safe while significantly enhanced in its replicative properties and overall ability to infect and kill glioma cells; 3) Enhancing Death Receptor Antibody Therapy for Anaplastic Gliomas will evaluate two new pro-apoptotic drugs, AT-101 and AT-406, together with a UAB developed, humanized anti-DR5 monoclonal antibody administered either intravenously or by convection enhanced delivery to induce apoptosis in tumor-associated endothelium and. glioma cells; and 4) Lysosomotropic Therapy of Anaplastic Gliomas will characterize blood-brain barrier-permeable analogues of chloroquine and fluoroquinolone that induce glioma cell autophagy. These projects will be supported by 5 Cores: 1) Administrative, 2) Brain Tumor Tissue, 3) Clinical Trials, 4) Biostatistics/Bioinformatics, and 5) Brain Tumor Animal Models. Our Career Development Program has recruited 2 new investigators to brain tumor translational research and will support up to 4 more. We will continue the: very successful Developmental Research Program that supported 15 investigators, .9 of whom were new to brain tumor research. All four of the proposed projects in this application were originally Developmental Projects. The University, School of Medicine and Comprehensive Cancer Center strongly support this SPORE application We will continue our multiple, active collaborations with other Brain Tumor SPOREs and will foster new interactions with other non-brain organ site cancer SPORE programs locally and nationally.